Z-amino-j



Patented Aug. 25 1953 UNITED sures rarest OFFICE 2-AMINO-3,4-DIHYDRO 1 POUNDS AND PROC ARATION QUI-NOXALINE COM- ESS FOR- THEIR PREP- Karl Pfister III, Westfield, and John Weijlard,

Maplewood, N. J., assi gnors to Merck & (30.,

Inc., Rahway, N. J a corporation of New Jersey No Drawing. Original a 1948, Serial No. 56,256.

plication April 19, 1952,

15 Claims.

This invention relates to an improved method generally applicable for the preparation of 2-aminoquinoxaline compounds which are important intermediates in the manufacture of the corresponding sulfaquinoxalines. The sulfaquinoxalines are bacteriostatic agents especially useful in veterinary medicine. They are also of value as antimalarial agents;

This application is a division of our copending application Serial No. 56,256, filed October 23, 1948.

Z-aminoquinoxaline, the precursor of sulfa- Which is ordinarily prepared by reacting orthophenylenediamine with alloxan.

low yields.

We have now discovered, however, a new and improved process for preparing Z-aminoquinoxaline which employs available and relatively inexpensive starting materials and which does not require the use of high pressures. We have further discovered that this novel process is genor alkoxy substituents.

This process may be chemically represented as follows:

N112 NHCHzCN CNH: H

N 2 NHz N 2 2 R wherein R1 and R2 are nuclear substituents of the class which consists of hydrogen, halo, alkyl and alkoxyradica pplication October 23",

Divided and this an- Serial No. 283,251

\ nobenzene,

The reactions indicated above are carried out as follows: a 1,2-diamino-benzene compound (I) is reacted with formaldehyde and hydrogen cyanide, or with glycolonitrile, or with a haloacetonitrile to produce an N(o-aminophenyl) glycine nitrile compound (2); this compound is then treated, in methanolic solution, with a strong base, thereby cyclizing the nitrile to produce the corresponding 2-amino-3A-dihydroquinoxaline compound (3) which is converted to the corresponding 2-aminoquinoxaline compound (4) by treatment with an oxidizing agent.

The LZ-diamino-benzene compounds, which can be used as starting materials: in practicing the present invention are those compounds which can be chemically represented as follows:

' NHZ,

wherein R1 and R2 are nuclear substituents of the class which consists of hydrogen, halo, alkyl compound with. glycolonitrile. This reaction is creased formation of the unwanted N,N-dicyanomethyl-o-phenylenediamine. For example, when an excess (about 10%) ofglycolonitrileis compound to however, the product obtainedis ordinarily of poor quality; it is therefore preferred to conduct the reaction by heating the reactants using water as the only solvent. The'reaction temperature critical in that no reaction occurs below about 45 C. and it has been found desirable to employ a reaction temperature of at least about 60 C. Although temperatures up to 95 C. have given excellent yields of good'quality material, it is ordinarily preferred to conduct the reaction at a temperature between 60 and 65 C. The pH duringthe reaction is also critical and should be adjusted to between about 6.0 and 7.0. No reaction occurs at pll:3; at pH values above about 7.0, the product is gummy. At a pH value within the range 6.0-6.2, the yield and quality of the product is satisfactory, but the condensation requires a temperature of at least about 90 C. It is therefore ordinarily preferred to employ a pH within the range of 5.5-7.0 under which conditions the reaction proceeds satisfactorily at the preferred temperature of 60-65" C. The optimum reaction time varies depending on the temperature and the pH; at 60-65 C., the reaction is ordinarily allowed to proceed for approximately two hours; at 9095 C. the reaction is about 80% completed in 8 minutes and is substantially complete in hour; no appreciable change in yield 7 results when the condensation time is increased from /2 hour to one hour at 90-95 C. When the reaction is carried out in water, the N- (o-aminophenyl) -glycine compound precipitates directly from the aqueous reaction mixture and is recovered by filtration. 7

Instead of glycolonitrile, a haloacetonitrile, such as 'chloroacetonitrile or bromoacetonitrile, can be reacted with the 1,2-diaminobenzene compound to produce the desired N- (o-aminophenyl) glycine nitrile compound. This reaction is con-.

veniently carried out by heating the diamine and the haloacetonitrile in the presence of a base, such as pyridine. It is ordinarily preferred to conduct the reaction by heating substantially equimolecular proportions of the reactants in solution in a lower aliphatic alcohol. It is important to avoid using an excess of haloacetonitrile since this results in appreciable formation of unwanted N,N-dicyanol,2-diaminobenzene by-products. The desired N-(o-aminophenyl) -glycine-nitrile compound is convenient- 1y separated from the reaction mixture by triturating said mixture with water (after evaporation of the alcohol when the reaction is carried out in this solvent) thereby precipitating the desired nitrile as a granular product.

The presently preferred process for accomplishing the conversion of the 1,2-diaminobenzene V the corresponding 'N-(o-aminophenyD-glycine-nitrile compound is by reacting said diamino-compound with formaldehyde and hydrogen cyanide. Asin the case of the reactions employing glycolonitrile or haloacetonitrile, it has been found best to employ approximately equimolecular proportions of reactants and, in particular, to avoid using an excess of formaldehyde and hydrogen cyanide, since this results in production of considerable'amounts of the unwanted N,l l-dicyano-1,2-diamino-benzene com- 7 pound,

pound, formaldehyde and sodium bisuliite is conveniently conducted in aqueous solution at a temperature, below about 60 C. The resulting mixture is then reacted, without further treatment, with a cyanide salt, the reaction being carried out at a, temperature of about -8 C. The N-(o-aminophenyl)-glycine nitrile compound thus produced is isolated directly from the reaction solution by cooling and crystallizing.

An improved modification of the above pro cedure involves reacting the 1,2-diaminobenzene compound with hydrogen cyanide and formaldehyde, said reaction being carried out in water or preferably water plus sufficient methanol. or other water-miscible lower aliphatic alcohol solvent to dissolve the diamine. The hydrogen cyanide utilized in the reaction is conveniently prepared in situ by reacting a cyanide salt with an acid. This is ordinarily accomplished by adding an aqueous solution of the cyanide salt to a mixture containing the 1,2-diaminobenzene compound, water or methanol, and aqueous hydrochloric acid. The quantities of reagents are preferably adjusted so that the pH of the resulting mixture is approximately 6.5-7.0. If desired, a smaller quantity of hydrochloric acid may be used in the initial mixture and the resulting alkaline cyanide solution acidified to a pH of 6.5-7.0 by the subsequent addition of hydrochloric acid. Instead of using a cyanide salt plus hydrochloric acid, the proper amount of hydrogen cyanide can be added to a mixture of the diamine and water; or diamine, water and methanol (or other lower aliphatic alcohol solvent), which automatically gives the proper pH. The reaction is preferably carried out by adding the formaldehyde to a mixture containing the other com the corresponding substituted N-(o-aminophenyl)-glycine nitrile compound having. the formula: r

NnomoN /NH2 R2 wherein R1 and R2 are nuclear substituents of the class which consists of hydrogen, halo, alkyl and alkoxy radicals. The relative positions of these substituent groupings in said nitrile compounds depends on the directive effect of said substituents on the entering cyanomethyl radical.

The cyclization of the N-(o-aminophenybglycine nitrile compound is accomplished by treating said N-(o-aminophenyl)-glycine nitrile compound with a methanolicsolution of a strong base, such as sodium hydroxide, potassiumhydroxide, sodium methylate, trimethylbenzylam a monium hydroxide, trimethylphenylammonium hydroxide, and the like. The cyclization is pref erably conducted under an inert atmosphere, such as nitrogen, but this is not essential. In fact, if desired, oxygen can be bubbled through the reaction mixture during the cyclization, thereby cyclizing the nitrile compound and, at the same time, oxidizing the intermediate 3,4- dihydroquinoxaline compound produced by said cyclization operation. It is ordinarily preferred, however, to conduct the cyclization under nonoxidizing conditions and then to oxidize the cyclization product in a separate oxidation step.

We have discovered that methanol is an essential component of the cyclization solution. Surprisingly enough, we have found that other lower aliphatic alcohols, such as ethanol, isopropanol and butanol are unsatisfactory for carrying out the cyclization reaction. Although it is possible to carry out the cyclization in aqueous methanol, we have found that the addition of water in excess of about 1% lowers the yield. We therefore prefer to employ substantially anhydrous methanol as the solvent for this reaction.

The base employed should be approximately equivalent stoichiometrically to the N-(o-aminophenyD-glycine nitrile. Amounts of base varying between 0.5 and 1.2 times the stoichiometric equivalent of the nitrile have given satisfactory results; cyclization employing molecular proportions of base below or above this range have resulted in decreased yield of the desired prodnot.

It has been found that the cyclization reaction can be carried out at temperatures within the range of about C. to 60 C. It is preferred, however, to conduct the cyclization at a temperature between about 25 C. and 55 0.; at which temperatures excellent tion product are obtained. The time required for the obtainment of maximum yield varies depending on the temperature and the proportion of solvent from at least hours for cyclizations conducted at 55 C. to about 72 hours for cyclizations at 25 C. Longer cyclization periods have little or no effect on the yield. The 2- amino-3,4-dihydroquinoxaline compound produced is conveniently isolated from the cyclization reaction mixture by evaporating most of the methanol and diluting the concentrate with water and cooling, whereupon said 2-amino-3,4- dihydroquinoxaline compound crystallizes and can be recovered by conventional means.

When the aforementioned substituted N-(oaminophenyl)-glycine nitrile compounds are treated according to the above-disclosed cyclization procedures, there are obtained the corresponding substituted 2-amino-3,4-dihydroquin-= oxaline compounds of the formula:

wherein R1 and R2 are nuclear substituents of the class which consists of hydrogen, halo, alkyl and alkoxy radicals.

These 2-amino-3,4-dihydroquinoxaline com-. pounds are converted to the corresponding 2- aminoquinoxaline compound by reacting said 2- amino-3,4=-dihydroquinoxaline compound with an oxidizing agent. The substituent groupings in yields of cycliza the previously disclosed halogenated, alkylated and alkoxy substituted 2-amino-3A-dihydroquinoxalines are not affected by the oxidation treatment with the result that. the product. in each case is the corresponding halogenated, alkylated or alkoxy substituted Z-amino-quinoxaline compound of the formula:

wherein R1 and R2 are nuclear substituents of the class which consists of hydrogen, halo, alkyl and alkoxy radicals;

The oxidizing agents ordinarily employed in this reaction include alkaline potassium ferricyanide, hydrogen peroxide under either acid or alkaline conditions, palladium-activated charcoal, ferric chloride, air, oxygen; it is ordinarily preferred to use hydrogen peroxide. When hydrogen peroxide is used as the oxidizing agent, it is preferably employed in conjunction with materials which are known to catalyze the decomposition of hydrogen peroxide, such as ferrous chloride. A list of such decomposition catalysts is given on page 24 of the text Reference Book of Inorganic Chemistry by Latimer and Hildebrand, N. Y., 1937, MacMillan Co.

The reaction between the 2-amino-3A-dihydroquinoxaline compound and alkaline potassium ferricyanide is best carried out by heating the reactants in aqueous solution, preferably at a temperature of approximately -85 C". When alkaline hydrogen peroxide is used as the oxidizing agent, any temperature from about 0 C. to over 70 C. can be employed. The reaction be tween the 2-amino-3,4-dihydroquinoxaline compound and hydrogen peroxide takes place spontaneously with evolution of heat and the reaction temperature is ordinarily maintained Within the preferred range by cooling the reaction mixture. If desired, however, the reaction mixture can be heated at the start of the reaction, thereby shortening the total reaction time. The time ordinarily required for the oxidation varies depending on the concentration of oxidizing agent, temperature of oxidation, etc., from about 30 minutes up to about 4 hours. Thereaction solution is then cooled and the desired z aminoquinoxaline compound crystallizes directly therefrom and is recovered by filtration or centrifugation.

The reaction between the 2-amino-3A-dihydroquinoxaline compound and palladium-activated charcoal is carried out by heating the re actants under reflux in tetralin solution. Under these conditions the reaction is substantially complete in approximately 1 hour. The catalyst is removed from the reaction mixture, while still hot, by filtration or oentrifugation, and the resulting tetralin solution is cooled to crystallize the desired Z-aminoquinoxaline compound. This crude product is recovered by filtration, washed with petroleum ether, and may be further purified by precipitation from its solution in aqueous mineral acid by the addition of an alkaline material.

When ferric chloride, hydrogen peroxide, or oxygen are employed as the oxidizingagent, the reaction is conveniently conducted byadding the oxidizing agent directly to the methanolic cyclization. soltuion, thus avoiding the need for isolating the 2-amino-3,4-dihydroquinoxaline coma pound. Moreover, a simultaneous cyclization and oxidation'can be accomplished thereby converting the o-(aminophenyD-glycine nitrile compound directly to the Z-aminoquinoxaline compound in a single operation.

The following examples illustrate methods of carrying out the present invention, but it is to be 7 understood that these examples are given by way of illustration and not of limitation.

Example 1 A suspension of 108 g. of o-phenylenediamine in 200 cc. of water was treated with a freshly made solution of 114.4 g. of sodium bisulfite and 90 g of 36% formaldehyde solution in 200 cc. of water. The mixture, which became slightly warm, was stirred for 2 hours, when solution became complete. After standing overnight at room temperature this solution was warmed to 60 C. for 4 hours and then treated with a solution of 54 g. of sodium cyanide in 100 cc. of water. The mixture was held at 80-85 C. for 30 7 Example 2 A mixture of 5.4 g. of o-phenylenediamine, 3.8 g. of chloroacetonitrile, 4.0 g. of pyridine and 50 cc. of'ethyl alcohol was heated under reflux for 3 hours. dry and granulated with water. Th 'precipitate was filtered off, washed and dried to give 2.3 g. (31.8% of theory) of crude N-(o-aminophenyl)- glycinenitrile; M. P. 102-105 C. A mixture of this product with material prepared as in Example 1 showed no depression in melting point.

Example 3 To a solution of 27.0 g. of o-phenylenediamine in 120 cc. of 2.5 N hydrochloric acid and 55 cc. of methanol was added 14.? g. of sodium cyanide. With the temperatures at 40-45 C., 20.8 g. of

66-38% solution of formaldehyde in water was added over l'minutes. Slight cooling was necessary to keep the temperature below 45 C. When'about of the formaldehyde was added,

faicrystalline precipitate of N-(o-aminophenyD- glycine nitrileappeared. The slurry was stirred for an hour'at room temperature and an hour at 0-5 C. before filtration. The residue was washed free of chloride with cold water, and recrystallized from 60 cc. of boiling isopropanol without being dried. After holding at 0-5 C. for 4-6 hours, the crystalline product was collected,

The solution was concentrated nearly washed with ice-cold isopropanol and dried. The

weight of the N-(o-aminophenyl) glycine nitrile was 30.6 g; or 83.1% of theory; M. P.=l04-106 C. By the, method of solubility analysis, this material was shown to be over 80% pure. The chief impurity was N,N dicyanomethyl-o-phenylenediamine. H Exa'mple4 250 odd water, 135.00 gms. 1.25 moles) of o-phenylenediamine and 145 gins. of 50% aqueous solution of glycolonitrile (1.25 moles) are mixed together and heated to about 30-35 C'. The initial pH of this solution which is about 6 is adjusted to 6.5-7.0 by the addition of 2.5 N sodium hydroxide solution, about 5 cc. being required. The resulting mixture (volume about 500 cc.) is then heated to (SO-65 C. and maintained at this temperature for approximately 2 hours. Mild heat evolution occurs for about 1 hour from the time the mixture reaches a temperature of approximately 60 C. The diamine dissolves at 50 C. and, after about 20 minutes at a temperature of 60-65" C., an oil separates which upon seeding becomes crystalline. After the 2 hour heating period, the reaction mixture is cooled to room temperature and maintained at this'temperature for at least 2 hours. The reaction mixture is then filtered and the crystalline product washed with three 100 cc. portions of water and dried at 4550 C. to produce l51l56.5 gms, of sandy, light brown N-(o-aminophenyl)-glycine nitrile; M. P. 10l-105 C.; yield a proximately 82-85% of theory.

Example 5 Equimoleoular quantities of o-phenylenediamine and glycolonitrile Were reacted togethersubstantially as described in Example 4, except that double the amount of water was employed. The quantity of N-(o-aminophenyl)-glycine nitrile'obtained was 84 /2% of that theoretically obtainable; M. P. 95-98 C.

7 Example 6 Example 7 Equimolecular amounts of o-phenylenediamine and glycolonitrile (50% aqueous solution in water) were heated together at a temperature of -95 C. for a period of 1 hour. The resulting mixture of N-,(o-aminophenyl) -glycine nitrile V was solid on cooling; M. P. 82-95 C. This product was recrystallized from isopropanol to produce N-(o-aminophenyl)-glycine nitrile; M. P.

104105 C.; yield approximately 63.3% of theory.

Example 9 o-Phenylenediamine was reacted with glycolo nitrile substantially as described in Example 4 except that only 94% of the theoretical equivalent of glycolonitrile was employed. As a result of the phosphoric acid added bythe manufac-- turer to stabilize the glycolonitrile, the pH of the starting material thus prepared was about 6.0-6.2. Under these slightly acid conditions, no

reaction occurred until the temperature reached 90% C. After /2 hour at 90 C. the reaction mix-- ture was treated as described in Example 4 to produce N-(o-aminophenyl) glycine nitrile in a yield of approximately 88.7% of theory; M. P. 88-89" C.

Example 10 Example 11 135.0 gms. (1.25 moles) of o-phenylenediamine was mixed with 250 cc. of water and the mixture heated to 90-95 C. 142.5 guns. of 50% aqueous solution of glycolonitrile (1.25 moles) was added to this solution while maintaining the reaction temperature at 90-95 C. The reaction mixture was then heated for an additional hour at 90-95 C. cooled to room temperature and the crude N-(o-aminophenyl)-glycine nitrile was isolated therefrom and dried substantially as described in Example 4; M. P. 91-93 C. Yield: 89.6% of theory. After recrystallization from isopropanol, the yield was 61.9% of substantially pure material; M. P. 104-105 C.

Example 12 Equimolecular amounts (1%; mole) of o-phenylenediamine and technical glycolonitrile (50% aqueous solution) were heated together, without additional diluent, at 90-95 C. for a period of approximately /2 hour. 75 cc. of isopropanol was added to the reaction mixture and the reaction mixture was cooled in ice and the crystalline product, which separated, recovered by filtration and dried to produce a yield of N-(o-aininop'henyD-glycine nitrile in a yield of approximately 74.5% of theory; M. P. 99-102 C.

This reaction was carried out as described above, except that the reaction mixture was heated at 90-95 C. for 1 hour. The yield and quality of the product was identical with that obtained in the foregoing experiment.

Example 13 135.0 gms. of o-phenylenediamine, 142.5 gms. of 50% aqueous solution of glycolonitrile and 250 cc. of water were mixed together and the pH of he mixture adjusted to about 6.5-7.0. The resulting mixture was then heated at a temperature of 9095 C. for a period of 1 hour, 50 cc. of isopropanol was added to the hot mixture and the resulting mixture was cooled to 0-5 C. The crystalline product which separated was recovered by filtration and dried at d-50 C. to produce crude N (o-aminophenyl) -glycine nitrile in a yield of approximately 78% of theory; M. P. 92-98C.

Example 14 V mole of o-phenylenediamine and A mole of glyoolonitrile (50% aqueous solution) were mixed with 55 cc. of methanol in 127 cc. of water and the pH of the mixture was adjusted to 6.5-7.0. The resulting mixture was heated at 60-65 C. for approximately 1 hour. The reaction mixture was cooled at 0 C.; the crystalline product which separated was recovered by filtration and dried to produce crude N-(o-aminopheny1) -glycine nitrile in a yield of 77% of theory; M. P. 88- 100 C.

Example 15 mole of o-phenylenediami-ne was dissolved in a mixture containing 24 cc. of methanol and 24 cc. of water and the pH of the solution was adjusted to 6.5-7.0. The resulting solution was heated to 75-80 C. and 4 mole of glycolonitrile was added to the resulting solution over a period of 40 minutes while maintaining the temperature of the resulting mixture at 75-80 C. The resulting solution was heated at this temperature for an additional hour period and then cooled to room temperature. The material which precipitated was recovered by filtration and dried to produce a crystalline product; M. P. below 75 C. assuming the product to be N-(o-aminophenyl) -glycine nitrile, the yield was approximately 63% of theory.

Example 16 A suspension of 51 g. of N-(o-aminophenyD- glycine nitrile in 400 cc. of methanol was treated with a solution of 8. 05 g. of sodium in 350 cc. of methanol and the mixture agitated until solution was essentially coir-.plete. After standing at room temperature for 48 hours a small amount of insoluble material was removed and themtrate concentrated dry in vacuo. The residue was slurried with 50 cc. of water (at 50 C.) cooled to 2 C. overnight, filtered, washed with ice water and dried. The weight of product obtained was 32.5 g.; M. P. 151 C.; yield 63.1% of theory.

Recrystallization from benzene-petroleum ether gave pale yellow needles of 2-amino-3,4 dihydroquinoxaline; M. P. 151 C. Anal. Calcd for CsH9N3: C, 65.27; H, 6.16; N, 28.54. Found: C, 65.12; H, 6.08.; N, 28.63.

Example 17 that the nitrile was dissolved in the sodium methylate solution at 60 C., the resulting solution maintained at 60 C. for one hour, and then allowed to stand overnight at room temperature. The yield of 2-ammo-3A-dihydroquinoxaline obtained by this procedure was 47% of theory.

Example 18 A mixture of 0.5 g. of 2-amino-3,4-dihydroquinoxaline, 0.05 g. of 10% palladium on Norit (an activated charcoal product) and 7 cc. of tetralin was refluxed for one hour. After filtration from the catalyst, the filtrate was cooled and the resulting preciuitate collected and washed with petroleum ether. This material was extracted with 2.5 N hydrochloric acid and the filtrate neutralized with sodium hydroxide. The pale yellow needles (weight 0.15 g.), which separated, melted at 154-156 C. and a mixture with authentic 2-aminoquinoxaline melted at the same temperature.

Example 19 Example 20 21.4 g. of 2-amino-3,4-dihydroquinoxaline was dissolved in 400 cc. of warm water, and a hot solution of 99 g. of potassium ferricyanide in games at can %'sodium hydroxide added -the temperature of the mixture was 70 C. Crystalliza- Example 21 A suspension of N-(o-aminophenyl) -glycine nntrile (7.4 g., 0.05 mole) in 65 cc. of methanol was treated with a solution of 3.1 g. (0.0755 mole) of sodium hydroxide in '75 cc. of methanol. After standing at room temperature for 24 hours, the solution was concentrated to dryness under vacuum (nitrogen atmosphere) and the residual material slurried with 30 cc. of water. The slurry was cooled to 0-5 C. overnight and then filtered, washed and dried. The direct yield of Z-amino-3,4-dihydroquinoxaline was 4.8 g. (65.6% of theory); M. P.=135-143 0.

Example 22 Cyclization was carried out as described in Example 21 andthe resulting solution was treated directly, without concentrating, with 0.1 g. finely ground FeCl24HzO and a hydrogen peroxide solution prepared by diluting 5.2 cc. of 30% hydrogen peroxide to 17 cc. with water. The methanol solution containing the iron catalyst was stirred and held at 25-30 C. while the hydrogen peroxide was added portionwise over a 2 hour period. 0.5 g. of activated charcoal (Norlt) was added and the mixture was filtered. The filtrate was concentrated to a volume of 50 00., 50 cc. of water added and the mixture again concentrated to a volume of 50 cc. The slurry was refrigerated overnight and then filtered, washed and dried. A direct yield of 4.5 g. o theory) was obtained. This material formed pale cream-colored needles which melted at 154.5-155.8 C. A slightly less pure second crop raised the yield to '70 of theory.

Example 23 A suspension of 7.4 g. (0.05 mole) of N-(oaminophenyD-glycine nitrile in 65 cc. of methanol was stirred and treated with a solution of 3.1 g. (0.055 mole) of KOH in 50 cc. of methanol (nitrogen atmosphere). The clear solution which soon resulted was allowed to stand at room temperature for 20 hours, then concentrated to dry- Example 24 N- (o-aminophenyl) -glycine nitrile was treated as described in Example 23, but with the addition of 1'7 cc. of water methanol volume). After standing 24 hours at room temperature a small sample was worked up to give 2-amino-3,4-dihydroquinoxaline; M. P.=l38-l42 C. The rest of the solution was oxidized as described in Example 22; A 43.8% yield of Z-aminoquinoxaline (M. P.=l55-l56 C.) was obtained. This yield is about lower than is obtained under anhydrous conditions.

A suspension of 6.6 g. (0.045 mole) of N-(oaminophenyD-glycine nitrile in 56 cc. of methanol was treated with a mixture of 22 g. of 38% aqueous solution of trimethylbenzylammonium hydroxide (0.05 mole), and 45 cc. of methanol and the mixture was allowed to stand at room temperature for 24 hours. One half of the result ing solution was oxidized as described in Example 22 using 0.03 finely ground FeCla4I-Iz0 and 2.3 cc. of 30% hydrogen peroxide (Superoxol) diluted to 7 cc. with water. After concentration to small volume and dilution with water, nicely crystalline I 2-aminoquinoxaline separated. The weight was 1.8 g. or 55% of theory; M. P.=153-155 C.

Example 26 7.73 g. (0.045 mole) of trimethylphenyl'ammonium chloride were added to a solution of 0.92 g. (0.04 mole) of sodium in 45 cc. of methanol. The sodium chloride which precipitated was removed by filtration and the methanol solution of trimethylphenylammonium hydroxide was added to a suspension of 6.6 g. (0.045 mole) of N-(oaminophenyl)-glycine nitrile in 56 cc. of methanol. After 24 hours at room temperature under a nitrogen atmosphere, the resulting solution was divided in halves and one of these oxidized as described in Example 22. The yield of Z-amino quinoxaline was 2.0 g. r (61.2% of theory); M. P.=155-l56C.

Example 27 A suspension of 66.3 g. (0.45 mole) of N-(oaminophenyl)-glycine nitrile methanol was stirred at room temperature, nitrogen was bubbled thru the mixture and a cold solution of 27.9 g. (0.497 mole) of potassium hydroxide in 450 cc. of methanol was added. The temperature remained unchanged and after about 10 minutes a clear solution resulted. The nitrogen stream and stirring was then discontinued and the resulting solution was allowed to stand in a closed flask at room temperature for 24 to 30 hours.

0.6 g. of finely grou d FC12.4H2O was added to the cyclization solution. 46.5 cc. of Superoxol (which contained 15.35 g. of hydrogen peroxide) was diluted to cc. with water and this solution was added in 15 cc. portions to the cyclization solution. The mixture was stirred and the temperature held between 25 and 30 C. by slight cooling. Between additions, the reaction mixture was stirred until the hydrogen peroxide was entirely consumed. After the addition was complete, the reaction mixture was stirred until a negative peroxide test was obtained; the total time required for the oxidation was approximately 2 to 3 hours.

3 g. of activated charcoal (Norit) was added to the'reaction mixture and the mixture was stirred for 15 minutes. The mixture was then filtered and the charcoal cake was washed with 50 cc. of methanol. The filtrate and washings were combined and concentrated under reduced pressure at a temperature of 40 C. until the volume was 500- 600 cc. 300 cc. of water was added and the distillation continued until the volume was again 600 cc. Crystallization occurred toward the end of the concentration and the slurry became so thick as to impede concentration if the inside temperature was allowed to fall below 40 C. The slurry was cooled to 0-5" G. for at least two hours before filtering. The product was washed free of hydroxyl ion with about 250 cc. of ice water and in 563 'cc. of

.Erample28 66.3 g. of N-(o-aminophenyl)-glycine .nitrile was treated as described in Example 27, except that theKOH-me'thanol solution was replaced by a sodium methylat-e solution prepared by adding 450 cc. of methanol, gradually at first, to 11.25 g. (0.489 atom) of sodium. After stirring at room temperature for 24 to 30 hours, the cyclization solution was oxidized as described in Example 25 to produce approximately 45 g. of substantially pure Z-aminoquinoxaline; M. P. 1i-' 'i.5-155 0.; yield approximately 68% of theory.

Example 29 0.6 g. of finely ground FeClzAHzO was added to a cyclization solution prepared from 66.3 g. of N (o-aminophenyl)-glycine nitrile as described in either Example 2'7 or 28. The resulting mixture was stirred at -5 C. (the low temperature minimizes loss of methanol and danger of an explosive air-methanol mixture) and dry carbon dioxidefree air was passed in slowly for 15 to .24 hours. 3 g. of activated charcoal (Norit) was added and the mixture worked up as described in Example 27 to produce about 45 g. of Z-ami-noquinoxaline. Yield approximately 68% of theory.

Example 30 A cyclization solution prepared as described in Example 28 from 17.1 g. (0.116 mole) of N-(oaminophenyl) -glycine nitrile in 145 cc. methanol plus 2.9 g. (0.126 atom) sodium in .116 ccrof methanol, Was treated with 2.5 N .HCl until the solution was no longer alkaline to phenolphthalein (ca. 53 cc. required). 68.5 g. of ferric chloride hexahydrate was added and the mixture let stand for 15 minutes (temperature rose a few degrees). 5.0 g. of filter cel (Supercel) andthen 30% sodium hydroxide were added until the mixture was alkaline to phenolpthalein (ca. 82 cc. required). The slurry of ferrous C. and filtered thru filter cel (Supercel). The residue was washed with '50 cc. of hot methanol. The filtrates were combined and concentrated until quite thick with precipitated 2aminoquinoxaline. The slurry was cooled to 05 C. for one hour, filtered and the filter cake washed free of sodium hydroxide and dried. The weight of 2-aminoquinoxaline was 2.8g. (46.5% of theory); M. 1 148-150 C.

Example 31 1.47 g. (.01 mole) of 2-amino-3,4-dihydroquinoxaline was dissolved in 6 cc. of water plus 4 cc. of 2.5 N HCl. 2.00 cc. of 30% aqueous hydrogen peroxide (Superoxol) was added and the mixture held at room temperature for minutes. 8 cc. additional 2.5 N HCl was added to the solution and the solution was then warmed to 80 C. for 2-3 minutes. The reaction solution was cooled and made alkaline with 4-5 cc. of 30% sodium hydroxide solution. The precipitated material was recovered by filtration, washed with water and dried. The weight of 2-aminoquinoxaline was 1.2 g. (82.0% of theory), M. P.==l49l52 C. A mixed M. P. with authentic 2-aminoquinoxaline was not depressed.

Example 32 A suspension of 7.3 g. of N-(o-aminophenyhglycine nitrile in 63 cc. of methanol was treated with a solution of 1.3 g. of sodium in 50 cc. of

hydroxide was heated to 75 methanol and the resulting mixture cooled to 0 C. and, with stirring, subjected to a stream of (dry carbon dioxide free air. After 48 hours 50 cc. of water was added and the reaction mixture was concentrated to a volume of about 50 cc. The slurry was refrigerated overnight and then filtered, washed and dried. The yield of Z-aminoquinoxaline of M. P.=149-154 C. was 3.7 g. or 51% of theory.

Example 33 .A cyclization solution, prepared as described in Example 27, from 1.47 g. (.01 mole) of N-(oaminophenyl-glycine nitrile in 12.5 cc. methanol plus 0.25 g. sodium in 10 cc. of methanol, was allowed to stand 24 hours and then stirred at room temperature while oxygen was bubbled through the solution. After 1 hours of bubbling, the solution was allowed to stand overnight and was then concentrated dry under vacuum. 10 cc. of water was added and the resulting slurry was cooled in ice for hour, filtered, the filter cake washed with water and dried. The yield of 2- aminoquinoxaline of M. P.=l53-155 C. was 0.82 g. or 56.5% of theory.

Example .34

4-methyl- 1,2 diaminobenzene, formaldehyde and hydrogen cyanide were reacted together according to substantially the same procedure employed in the case of o-phenylenediamine and described in Example 3. The crystalline product thus obtained was dried to produce the corresponding N-(Z-amino-methylphenyl-glycine nitrile in a yield of approximately 86.3% of theory.

16.1 gms. of this ntrile was added to a solution containing 6.2 gms. of potassium hydroxide dissolved in cc. of methanol, and the resulting solution was allowed to stand under a nitrogen atmosphere at room temperature for about 48 hours thereby forming the corresponding 2- amino methyl 3,4 dihydroquinoxaline. compound can be isolated, if desired by evaporating the methanol under reduced pressure, triturating the residue with water, filtering the crystalline slurry thus obtained and drying the crystalline product.

0.13 gm. of finely ground ferrous chloride tetrahydrate was, however, added to the methanolic reaction solution without further treatment thereof, and a solution of 103 cc. of Superoxol diluted to 35 cc. with water was then added to this reaction solution over a period of 1 hour While maintaining the reaction temperature at approxima-tely 30 C. The reaction mixture was then stirred for an additional 1 hour period and a trace of sodium sulfite was then added thereto to de-. stroy excess hydrogen peroxide. The solution was treated with activated charcoal, filtered and evaporated to a volume of approximately 100 cc. About 65 cc. of water was then added to this conand the resulting solution again concentrated to 100 cc. whereupon a crystalline product separated. This product was rewashed and dried to produce about 9.5 gms. of the corresponding Z-aminomethylquinoxaline; M. P. -173 C.

This product was purified by recrystallization from benzene to produce substantially pure material; M. P. 1'74-1755" C. Anal. Calcd for CQHQNS; C, 67.90; H, 5370. Found: C, 68.01; H, 5.65.

Example .35

3 methyl-lg2-diaminobenzene, formaldehyde and hydrogen cyanide were reacted together according to substantially the same procedure employed in the case of o-phenylenediamine 'and described in Example 3. The'crystalline product thus obtained was dried to produce the corresponding N-(2-amino-methylphenyl) -glycine nitrile in a yield of approximately 61% of theory; M. P. 74-84" C.

24.75 gms. of this nitrile was dissolved in 92 cc. of menthanol containing 8.6 gms. of potassium hydroxide and the solution was allowed to stand at room temperature under nitrogen for about 72 hours. The dihydroquinoxaline present in this solution is isolated by evaporating the nitrile under reduced pressure, triturating the residual material with water, filtering the crystalline slurry thus obtained, and drying to produce the corresponding 2-amino-methyl-3,4-dihydroquinoxaline. I

Instead of isolating the dihydroquinoxaline, however, the methanolic reaction solution obtained above was oxidized as follows: 0.2 gm. of ferrous chloride tetrahydrate was added to the reaction solution, and a solution of 15.8 cc. of Superoxol (diluted to 51 cc. with water) was then added to this reaction solution over a period of 1 hour while the temperature was maintained at approximately 30 C. The reaction mixture was then stirred for an additional 1 hour period and a trace of sodium sulfate was added thereto to destroy excess hydrogen peroxide. The solution was treated with activated charcoal, filtered and evaporated to a volume of approximately 150 cc. About 75 cc. of water was then added-to this solution and the resulting solution again concentrated to about 150 cc. whereupon a crystalline product separated. This product was recovered by filtration, washed and dried to produce a 51% yield of the corresponding 2-amino methylquinoxaline; M. P.

' 129131 C. This product was purified by recrystallization from benzene to produce substantially pure 2-amino-methylquinoxaline monohydrate; M. P. 135-136 Anal. Calcd for C9I-I11N3O: C, 61.10; H, 6.26; N, 23.70. Found: C, 61.33; H, 5.95; N, 23.30. After drying at 100 C. at 1-2 mm. pressure, anhydrous material of the same M. P. was obtained. Anal. C'alcd for C9H9N3: C, 67.90; H, 5.70. Found: C, 68.01; H,

According to this process only one isomer (either the or 8 methyl derivative) was obtained. From stereochemical considerations it appears likely that the particular isomer obtained according to the foregoing procedure was 2-amino-S-methylquinoxaline. The corresponding precursors would therefore be 2-amino-8- methyl-3,4-dihydroquinoxaline and N-(2-amino- 3-methylphenyD-glycine nitrile (M. P. 74-84 C.). The other isomer, which has been prepared by a modified procedure, melts at 202-203 C. and appears to be 2-amino-5-methyl-quinoxaline.

Example 36 3.56 gms. (0.25 mole) of 4-chloro-1,2-diaminobenzene were heated with 2.85 gms. (0.25 mole) '16 M. P. 81.5-85.5 C.; yield approximately 31% of theory.

2.6 gms. of this nitrile was mixed with 0.9 gm. of potassium hydroxide and 23 cc. of methanol and the resulting solution allowed to stand under nitrogen for 3 days.

The resulting solution is evaporated to dryness under reduced pressure, the residual material triturated with water and the crystalline product filtered and dried to'produce a mixture of 2-amino-6-chloro-3,4-dihydroquinoxaline and 2-amino-7-chloro3,4-dihydroquinoxaline.

Alternatively 0.2 gm. of finely ground ferrous chloride tetrahydrate were added to the reaction solution followed by a solution containing 1.5 cc. of Superoxol diluted to 5 cc. with water. After the resulting solution had been allowed to stand for 15 minutes, crystals began to separate and after 45 minutes all of the peroxide had been consumed. Two different isomeric products were obtained by fractional crystallization of this reaction mixture; the first (27% of theory) melted at 215-216 C. and after purification by recrystallization from alcohol yielded needles melting at 217-2l9 C. The second crop (22% 'of theory) recovered from this liquor melted at Analysis of the isomer melting at 215-216 C.

,Calcd for CsHcNsCl; C, 53.49; H, 3.73. Found:

Example 37 4-methoxy-1,2-diaminobenzene, formaldehyde and hydrogen cyanide were reacted together according to substantially the same procedure employed in the case of o-phenylenediamine and described in Example 3. The crude material obtained according to this procedure was gum from which the corresponding N-(2-amino-methoxyphenyl) -glycine nitrile was obtained as a semisolid in about 50% yield after digestion with chloroform and benzene mixtures.

A solution containing about 17.7 gms. of this nitrile and 6.2 gms. of potassium hydroxide in 210 cc. of methanol was allowed to stand at room temperature under nitrogen for 3 days.

This solution is evaporated under reduced pressure, the residual material is triturated with water and the crystalline product thus obtained recovered by filtration and dried to produce the corresponding crude 2-amino-methoxy3,4-dihydroquainoxaline.

Instead of isolating the dihydroquinoxaline compound, however, 0.13 gm. of finely ground ferrous chloride tetrahydrate was added to the methanolic reaction solution without further treatment thereof, and a solution containing 10.3 cc. of Superoxol diluted to 33 cc. with water was then added to this reaction solution over a period of 1 hour while maintaining the reaction temperature at approximately 30 C. The reaction mixture was then stirred for an additional 1 hour period and a trace of sodium sulfite was added approximately 72% of theory. This product was purified by repeated precipitation from dilute hydrochloric acid solution followed by recrystallization from alcohol to produce pale yellow feathery needles; M. P. 216.5-217.5 C. Anal. Calcd for CQHSJONSI C, 61.70; H, 5.20. Found: C, 61.99; H, 5.21.

Example 38 66.3 g. of purified N-(o-aminophenyl)-g1ycine nitrile, having a M. P. of 1l0-111 C. and a purity of about 95% by solubility analysis, was dissolved in 600 cc. of methanol containing 13.5 g. of potassium hydroxide and the solution was maintained at 35-40 C. for 17 hours under a nitrogen atmosphere. The resulting mixture was oxidized using hydrogen peroxide and ferrous chloride in the usual manner, thereby producing 2-amioquinoxaline (M. P.=156-157.5 C.) which was isolated in a yield of 85% of theory.

Various changes and modifications may be made in carrying out the present invention without departing from the spirit and scope thereof. Insofar as these changes and modifications are within the scope of the annexed claims, they are to be considered as part of our invention.

We claim:

1. The process of preparing 2-amino-3A-dihydroquinoxaline compounds which comprises reacting a methanolic solution of a strong base with the corresponding N-(o-aminophenyl)-glycine nitrile compound having the formula:

NHOHION wherein R1 and R2 are nuclear substituents selected from the class which consists of hydrogen, halo, alkyl and alkoxy radicals.

2. The process of preparing 2-amino-3,4-di hydroquinoxaline which comprises reacting N- (o-aminophenyl) -glycine nitrile with a methanolic solution of a strong base.

3. The process of preparing 2-amino-6-chloro- 3,4-dihydroquinoxaline which comprises reacting N-(2-amino-5-chlorophenyl) -g1ycine nitrile with a methanolic solution of a strong base.

4. The process of preparing 2-amino-7-chloro- 3,4-dihydroquinoxaline which comprises reacting N-(2-amino-4-ch1orophenyl) -glycine nitrile with a methanolic solution of a strong base.

5. The process of preparing Z-amino-BA-dihydroquinoxaline which comprises reacting N-(oaminophenyll-glycine nitrile with a methanolic solution of an alkali metal 'alcoholate.

6. The process of preparing 2-amino-3,4-dihydroquinoxaline which comprises reacting N-(oaminophenyD-glycine nitrile with a methanolic solution of an alkali metal hydroxide.

'7. The process of preparing 2-amino-3,4-dihydroqiunoxaline which comprises reacting N-(oaminophenyl) -g1ycine nitrile with a substantially anhydrous methanolic solution of potassium hydroxicle.

8. The process of preparing 2-amino-8-methyl- 3,4-dihydroquinoxaline which comprises reacting N-(2-amino 3 methylphenyl) glycine nitrile with a methanolic solution of a strong base.

9. The process which comprises reacting N -(2- amino-methoxyphenyl) -glycine nitrile with a methanolic solution of a strong base to produce 2-amino-methoxy-3,4-dihydroquinoxaline.

10. 2 amino 3,4 dihydroquinoxaline compounds of the formula:

\CHI 1 ill-NH: R2 N wherein R1 and R2 are nuclear substituents of the class which consists of hydrogen, halo, alkyl and alkoxy radicals.

11. 2-amino-3A-dihydroquinoxaline.

12. Z-amino-6-chloro-3,4-dihydroquinoxaline.

l3. 2-amino-'7--chloro-3,4-dihydroquinoxaline.

14. 2-amino-8-methyl-3,4-dihydroquinoxaline.

l5. 2-amino-methoxy-3,4-dihydrouuinoxaline.

KARL PFISTER III.

JOI-IN WEIJLARD.

No references cited. 

1. THE PROCESS OF PREPARING 2-AMINO-3,4-DIHYDROQUINOXALINE COMPOUNDS WHICH COMPRISES REACTING A METHANOLIC SOLUTION OF A STRONG BASE WITH THE CORRESPONDING N-(O-AMINOPHENYL)-GLYCINE NITRILE COMPOUND HAVING THE FORMULA: 